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ABSTRACT: RH2 is a novel oncolytic herpes simplex virus type 1 (HSV-1) produced by simultaneous infection with a neurovirulent gamma 34.5 gene-deficient HSV-1 R849 derived from strain F and a spontaneously occurring, fusogenic HSV-1 HF in cell culture. The genome of RH2 was studied using Genome Sequencer FLX (GS FLX). Total nucleotides of RH2 were 149,643 bp and LacZ inserted into the gamma 34.5 gene of R849 was demonstrated. Comparison of open reading frames (ORF) revealed that RH2 had 100 % identity with strain F in 21/58 (36.2%) genes of unique long (UL) and 1/13 (7.7%) genes of unique short (US). RH2 had 100% amino acid identity with HF10 in 24/58 (41.4%) genes of UL and 9/13 (69.2%) gene of US. Twelve genes including UL27 (gB), US4 (gG) and UL6 (gD) had amino acid changes unique to RH2. Amino acid changes in gB occurred at positions 459 (T-A) and 817(L-P). Other unique features were the amino acid missing in UL36 (VP1/2) and UL46 (VP11/12). RH2 is a HF10-based vector, preserving the fusogenic amino acid changes of gB, but lacking the gamma 34.5 gene. RH2 is expected to be a version of HF10 useful for brain tumors as well as oral squamous cell carcinoma (SCC). Spontaneously occurring HSV-1 mutants may be useful clinically, because the genome sequences can be easily determined by the genome sequence system.
Journal of General Virology 12/2012; · 3.36 Impact Factor
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ABSTRACT: The authors previously created HAp or CaCO(3) formed on or in agarose gels (HAp and CaCO(3) gels, respectively) as biocompatible and biodegradable bone graft materials. However, these gels have limitations for bone regeneration. Mesenchymal stromal cells (MSCs) have osteogenic potential and are considered useful for bone tissue engineering. The purpose of this study was to clarify the osteogenic abilities of MSCs loaded in HAp or CaCO(3) gels (MSC/HAp and MSC/CaCO(3) gels, respectively) using a rat cranial defect model compared to HAp and CaCO(3) gels alone. HAp, CaCO(3) , MSC/Hap, and MSC/CaCO(3) gels were prepared for in vivo analyses and implanted into full-thickness bone defects created in the rat cranium. All samples were assessed radiologically and histologically at 4 and 8 weeks after implantation. Using microfocus-computed tomography, an increase in bone formation was observed in the MSC-loaded gels compared to the gels alone. In addition, peripheral quantitative computed tomography revealed higher bone mineral contents in the MSC-loaded gels compared to the gels alone. After transmission X-ray diffraction analyses, the degree of apatite c-axis orientation as a bone quality index of newly formed bone in the MSC-loaded gels was close to that of living cranial bone. Histologically, more extensive bone formation was detected in the MSC-loaded gels compared to gels alone. Overall, MSC/HAp and MSC/CaCO(3) gels showed equivalent efficacy for bone regeneration. These findings demonstrate that loading of MSCs into the gels strengthened their osteogenic ability and improved the quality of the newly formed bone. As a result, MSC-loaded gels could represent viable therapeutic biomaterials for bone tissue engineering. Copyright © 2012 John Wiley & Sons, Ltd.
Journal of Tissue Engineering and Regenerative Medicine 02/2012; · 3.28 Impact Factor
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ABSTRACT: Ultrasound has been shown to increase the efficiency of gene expression from retroviruses, adenoviruses and adeno-associated viruses. The effect of ultrasound to stimulate cell membrane permeabilization on infection with an oncolytic herpes simplex virus type 1 (HSV-1) was examined.
Vero monkey kidney cells were infected with HSV-1 and exposed to 1 MHz ultrasound after an adsorption period. The number of plaques was significantly greater than that of the untreated control. A combination of ultrasound and microbubbles further increased the plaque number. Similar results were obtained using a different type of HSV-1 and oral squamous cell carcinoma (SCC) cells. The appropriate intensity, duty cycle and time of ultrasound to increase the plaque number were 0.5 W/cm², 20% duty cycle and 10 sec, respectively. Ultrasound with microbubbles at an intensity of 2.0 W/cm², at 50% duty cycle, or for 40 sec reduced cell viability.
These results indicate that ultrasound promotes the entry of oncolytic HSV-1 into cells. It may be useful to enhance the efficiency of HSV-1 infection in oncolytic virotherapy.
Virology Journal 09/2011; 8:446. · 2.34 Impact Factor
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ABSTRACT: R849 is a neurovirulent γ₁34.5 gene-deficient form of herpes simplex virus type 1 (HSV-1) and has LacZ genes at the deleted sites of the γ₁34.5 gene. HF is a spontaneously occurring, fusogenic HSV-1 strain. The purpose of this work was to generate a virus that has the syncytial character of HF, while preserving the γ₁34.5 gene inactivation profile of R849 virus.
Vero cells were infected with R849 and HF simultaneously and two viruses, RH1 and RH2, expressing the LacZ gene and inducing extensive cell fusion were selected. A polymerase chain reaction (PCR)-based analysis suggested that one copy of the γ₁34.5 gene is lost in RH1, whereas both copies are lost in RH2, and that the γ₁34.5 gene is replaced by a R849-derived DNA fragment with the LacZ gene. These viruses produced larger plaques and more progeny than the parental viruses. Infection with RH2 decreased the viability of oral squamous cell carcinoma (SCC) cells most strongly. When RH2 was injected into xenografts of oral SCC in nude mice, multinucleated cells were produced and the growth of the tumors was suppressed significantly.
These results indicate that novel oncolytic HSV-1 vectors can be produced with the genetic background of the oncolytic HSV-1 HF, and that RH2 is deficient in γ₁34.5 genes and shows extensive cytopathic effects in oral SCC cells. RH2 may be useful in oncolytic virotherapy for oral SCC.
Virology Journal 06/2011; 8:294. · 2.34 Impact Factor
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ABSTRACT: To clarify the role of p53 in boron neutron capture therapy (BNCT) for oral squamous cell carcinoma (SCC), the effect of BNCT on oral SCC xenografts with either wild-type or mutant-type p53 was examined.
Oral SCC cells expressing either wild-type (SAS/neo) or mutant-type p53 (SAS/mp53) were used to produce nude mouse tumours. Tumour-bearing mice received boronophenylalanine (BPA) at a dose of 250 mg/kg and tumours were exposed to neutron irradiation.
After BNCT, the growth of SAS/neo and SAS/mp53 tumours was suppressed remarkably and all tumours became undetectable within two weeks. However, three of six SAS/mp53 tumours showed regrowth in two months. Histological examination of BNCT-treated tumours revealed chromosomal condensation, micronucleation, nuclear segmentation and intra- and intercelluar vacuolation. Notably, multinucleated giant cells appeared in SAS/mp53 tumours early after BNCT, suggesting mitotic catastrophe. In SAS/mp53 tumours treated with BNCT, a rapid decrease in phosphorylated cell division cycle 2 (cdc2) and a high level of cyclin B1, required for premature mitosis, were observed.
These results indicate that BNCT suppressed oral SCC xenografts in nude mice efficiently, but cells survived in mutant-type p53 tumours. BNCT induces multinucleation which represents prestage of apoptosis or necrosis in oral SCC with mutant-type p53, but it may be also associated with the recurrence of BNCT-treated tumours.
International Journal of Radiation Biology 12/2010; 87(3):293-301. · 2.28 Impact Factor
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ABSTRACT: Geranylgeranyltransferase I is required for the prenylation of the small GTPases. The effect of GGTase I inhibitors (GGTIs) on oral squamous cell carcinoma (SCC) cells was examined.
The GGTI-treated cells were examined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay, flow cytometric analysis, transwell chamber assays, and immunofluorescent staining. Small GTPases were detected by immunoblot analysis, and siRNA were used for silencing RalA and RalB.
GGTI suppressed the proliferation of oral SCC cells and induced cell cycle arrest at G(1), but the sub-G(1) fraction was small. The expression of the cyclin-dependent kinase (CDK) inhibitor p21(Waf1/Cip1), but not p27(Kip1), was markedly increased by GGTI. There was an apparent increase in the expression and reduction in the membrane localization of RhoA and RalB, but not Ras and RalA. Assays with transwell chambers and wound healing and invasion revealed the migrative and invasive capabilities of SAS cells to be inhibited by GGTI. Actin filaments were rearranged and stress fibers and peripheral cell processes were lost, accompanying cell rounding. siRNA for RalB, but not RalA, significantly suppressed the migration of SAS cells.
These results suggest that GGTI inhibits the geranylgeranylation of RhoA and increases the p21(Waf1/Cip1) level, resulting in cell cycle arrest at G(1) to decrease cell proliferation, and that of RalB to suppress the migration and invasion by oral SCC cells. GGTIs may be useful as inhibitors of invasion and metastasis in cases of oral SCC.
Cancer Chemotherapy and Pharmacology 11/2010; 68(3):559-69. · 2.83 Impact Factor
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ABSTRACT: The Wnt/β-catenin pathway plays a critical role in cell proliferation and oncogenesis. To clarify the role of cytoplasmic accumulation of β-catenin in oral squamous cell carcinoma (SCC), the cDNA of a mutant form of β-catenin that lacks the entire region with the glycogen synthase kinase-3 β (GSK-3β)-specific phosphorylation site was transfected into Ca9-22 cells whose β-catenin had been expressed predominantly at the membrane, and permanent cell lines expressing aberrant β-catenin in the cytoplasm and nucleus were produced. These transfectants, C1 and C5, proliferated at similar rates to the parental Ca9-22 cells, but the cell morphology changed from polygonal to spindle-shaped and close cell-cell interaction was lost. These mutant β-catenin-expressing cells exhibited a significantly higher invasion/migration capacity than wild-type Ca9-22 cells. The transcriptional activities of this mutant β-catenin form was enhanced in these cells which could be demonstrated by an elevated level of the transcription factor T-cell factor (Tcf)/lymphoid enhancer factor (Lef)-dependent reporter gene activity as well as by the up-regulation of Wnt/β-catenin target gene matrix metalloproteinase (MMP)-7. Moreover, we observed the redistribution of E-cadherin, the rearrangement of actin filaments, and the elevation of active Rho family members, Cdc42 and Rac. These results suggest that aberrant cytoplasmic accumulation of β-catenin can induce Tcf/Lef-mediated transcriptional activity, up-regulate MMP-7, and induce epithelial and mesenchymal transition (EMT). This would enhance the invasion and migration of oral SCC cells.
International Journal of Oncology 11/2010; 37(5):1095-103. · 2.40 Impact Factor
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ABSTRACT: Boron neutron capture therapy (BNCT) is a selective radiotherapy, being effective for the treatment of even advanced malignancies in head and neck regions as well as brain tumors and skin melanomas. To clarify the role of p53 gene, the effect of BNCT on oral squamous cell carcinoma (SCC) cells showing either wild- (SAS/neo) or mutant-type (SAS/mp53) p53 was examined.
Cells were exposed to neutron beams in the presence of boronophenylalanine (BPA) at Kyoto University Research Reactor. Treated cells were monitored for modulations in colony formation, proliferation, cell cycle, and expression of cell cycle-associated proteins.
When SAS/neo and SAS/mp53 cells were subjected to BNCT, more suppressive effects on colony formation and cell viability were observed in SAS/neo compared with SAS/mp53 cells. Cell cycle arrest at the G1 checkpoint was observed in SAS/neo, but not in SAS/mp53. Apoptotic cells increased from 6 h after BNCT in SAS/neo and 48 h in SAS/mp53 cells. The expression of p21 was induced in SAS/neo only, but G2 arrest-associated proteins including Wee1, cdc2, and cyclin B1 were altered in both cell lines.
These results indicate that oral SCC cells with mutant-type are more resistant to BNCT than those with wild-type p53, and that the lack of G1 arrest and related apoptosis may contribute to the resistance. At a physical dose affecting the cell cycle, BNCT inhibits oral SCC cells in p53-dependent and -independent manners.
Radiation Oncology 12/2009; 4:63. · 2.32 Impact Factor
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ABSTRACT: The main objective of this study was to evaluate the biological behavior of Hydroxyapatite (HAp)/agarose and calcium carbonate (CaCO3)/agarose composite gels by an alternate soaking process used for the treatment of surgically produced bone defects in rat cranium. We designed the following four groups: (i) HAp (HAp/agarose composite gel), (ii) CaCO3 (CaCO3/agarose composite gel), (iii) Agarose (bare agarose gel), and (iv) Defect (no filling materials). We subdivided (i) (ii) (iii) into two application types as a (I) Homogenized Group (homogenized materials) and a (II) Disk Group (disk shaped materials). We assessed samples by radiological and histological analyses 0, 4, and 8 weeks after implantation. The results indicated that the composite gels showed higher radiopacity in microfocus-computed tomography (muCT) images and showed higher volume in quantitative analyses using Dual Energy X-ray Absorptiometry (DEXA) and Peripheral Quantitative Computed Tomography (pQCT) than the Agarose and Defect groups. The histological examination showed characteristic images due to each application form. Consequently, HAp and CaCO3/agarose composite gels can be expected to accelerate the speed of producing more new bone associated with osteogenesis. These novel biomaterials play an important role as an alternative biocompatible and biodegradable bone grafting filler material for autogenous bone.
Journal of Biomedical Materials Research Part A 09/2009; 93(3):965-75. · 2.63 Impact Factor
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Itsuro Kato,
Yusei Fujita,
Akira Maruhashi,
Hiroaki Kumada,
Masatoshi Ohmae,
Mitsunori Kirihata,
Yoshio Imahori,
Minoru Suzuki,
Yoshinori Sakrai,
Tetsuro Sumi, Soichi Iwai,
Mitsuhiro Nakazawa,
Isao Murata,
Hiroyuki Miyamaru,
Koji Ono
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ABSTRACT: It is necessary to explore new treatments for recurrent head and neck malignancies (HNM) to avoid severe impairment of oro-facial structures and functions. Boron neutron capture therapy (BNCT) is tumor-cell targeted radiotherapy that has significant superiority over conventional radiotherapies in principle. We have treated with BNCT 42 times for 26 patients (19 squamous cell carcinomas (SCC), 4 salivary gland carcinomas and 3 sarcomas) with a recurrent and far advanced HNM since 2001. Results of (1) (10)B concentration of tumor/normal tissue ratios (T/N ratio) of FBPA-PET studies were SCC: 1.8-5.7, sarcoma: 2.5-4.0, parotid tumor: 2.5-3.7. (2) Therapeutic effects were CR: 12 cases, PR: 10 cases, PD: 3 cases NE (not evaluated): 1 case. Response rate was 85%. (3) Improvement of QOL such as a relief of severe pain, bleeding, and exudates at the local lesion, improvement of PS, disappearance of ulceration, covered with normal skin and preserved oral and maxillofacial functions and tissues. (4) Survival periods after BNCT were 1-72 months (mean: 13.6 months). Six-year survival rate was 24% by Kaplan-Meier analysis. (5) Adverse-events were transient mucositis and alopecia in most of the cases; three osteomyelitis and one brain necrosis were recognized. These results indicate that BNCT represents a new and promising treatment approach for advanced HNM.
Applied radiation and isotopes: including data, instrumentation and methods for use in agriculture, industry and medicine 05/2009; 67(7-8 Suppl):S37-42. · 1.09 Impact Factor
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ABSTRACT: The protein kinase C (PKC) inhibitor safingol increased rounding and detachment of human oral squamous cell carcinoma (SCC) cells in monolayer cultures. When dissociated cells were incubated in the presence of safingol, cell adhesion was prevented and cell viability was lost gradually, while most cells survived in the absence of safingol even if their attachment was blocked by coating the culture plates with polyhydroxyethyl methacrylate. Flow cytometric analysis and agarose gel electrophoresis of cellular DNA revealed an increase in the proportion of sub-G(1) cells and DNA fragmentation, indicating that safingol induced apoptosis of dissociated cells. During the induction of apoptosis in cell suspensions by safingol, there was an increase of the pro-apoptotic BH-3 only protein Bim and decrease of pro-survival Bcl-2 family proteins Bcl-xL and mitochondrial pro-apoptogenic factor endonuclease G translocated to the nucleus. The level of phosphorylated focal adhesion kinase (FAK) required for cell survival also rapidly decreased, followed by a decrease in the protein level. The introduction of siRNA against PKCalpha into SAS cells resulted in an increase of Bim, a decrease of Bcl-xL, the translocation of endonuclease G, and a decrease in the phosphorylation of FAK. These results suggest that Bim, Bcl-xL, FAK and endonuclease G are involved in safingol-induced apoptosis of detached oral SCC cells. Safingol can be used to induce apoptosis with cell detachment, anoikis, of oral SCC cells.
Apoptosis 03/2009; 14(3):287-97. · 4.07 Impact Factor
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ABSTRACT: The effects of boronophenylalanine (BPA)-mediated boron neutron capture therapy (BNCT) on the growth potential and cell cycle of human oral squamous cell carcinoma (SCC) cells were examined.
SAS cells expressing a functional wild-type p53 were exposed to neutron beams in the presence of BPA and growth potential was measured by colony formation assay and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The cell cycle and cell cycle-related proteins were examined by flow cytometry and immunoblot analysis.
BNCT affected the colony-forming ability and viability of SAS cells. In the flow-cytometric analysis of BNCT-treated cells, the cell cycle was arrested at the G1 and G2 checkpoints, and sub-G1 cells appeared. Apoptotic cells were detected by nuclear DNA staining. Immunoblot analysis revealed the phosphorylation of p53, up-regulation of p21, and down-regulation of retinoblastoma (Rb) gene protein at 6 h after BNCT. Twelve hours after BNCT, the up-regulation of Wee1, phosphorylation of cdc2, and up-regulation of cyclin B1 were observed. Cleavage of poly (ADP-ribose) polymerase (PARP) occurred from 6 h after BNCT.
These results indicate that the early inhibitory effect of BNCT on the growth of human oral SCC cells can be ascribed to arrest at the G1 and G2 checkpoints and apoptosis associated with G1 arrest.
International Journal of Radiation Biology 04/2008; 84(3):191-9. · 2.28 Impact Factor
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ABSTRACT: It was reported that elevation of the intracellular concentration of free Ca2+ ([Ca2+]i) by a calcium ionophore increased the release of herpes simplex virus type 1 (HSV-1). Freely diffusible hydrogen peroxide (H2O2) is implied to alter Ca2+ homeostasis, which further enhances abnormal cellular activity, causing changes in signal transduction, and cellular dysfunction. Whether H2O2 could affect [Ca2+]i in HSV-1-infected cells had not been investigated.
H2O2 treatment increased the amount of cell-free virus and decreased the proportion of viable cells. After the treatment, an elevation in [Ca2+]i was observed and the increase in [Ca2+]i was suppressed when intracellular and cytosolic Ca2+ were buffered by Ca2+ chelators. In the presence of Ca2+ chelators, H2O2-mediated increases of cell-free virus and cell death were also diminished. Electron microscopic analysis revealed enlarged cell junctions and a focal disintegration of the plasma membrane in H2O2-treated cells.
These results indicate that H2O2 can elevate [Ca2+]i and induces non-apoptotic cell death with membrane lesions, which is responsible for the increased release of HSV-1 from epithelial cells.
Virology Journal 02/2006; 3:62. · 2.34 Impact Factor
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ABSTRACT: The Wnt pathway is involved in carcinogenesis and three regulatory genes of the Wnt pathway, APC, beta-catenin and Axin are mutated in some primary human cancers. Mutations in these genes can impair the down regulation of beta-catenin, which results in the stabilization of beta-catenin, accumulation of free beta-catenin and subsequent activation of the Wnt pathway. To clarify the genetic alterations of components of the Wnt pathway in oral squamous cell carcinoma (SCC), we examined mutations in the APC, beta-catenin and Axin genes and subcellular localization of beta-catenin.
20 oral SCC tissues and four cell lines derived from oral SCC were used. Mutational analysis was performed by a single-strand conformation polymorphism (SSCP) method and direct sequencing analysis. The samples were also examined by immunohistochemical staining and immunoblot analysis.
In 3 of 4 cell lines, mutations were observed in the APC and Axin1 genes without amino acid substitutions. In a clinical sample, a mutation in the Axin1 gene was detected; a T insertion at codon 250 resulted in the formation of a stop codon at codon 259. In addition, cytoplasmic accumulation of beta-catenin was observed in 3 (75%) of 4 cell lines and 18 (90%) of 20 cancer tissue samples.
The Axin1 gene may be one of the mutational target in oral SCC. In addition, the cytoplasmic accumulation of beta-catenin is a common characteristic of oral SCC, but is not closely associated with mutational alterations in the APC, beta-catenin and Axin1 genes.
Journal of Cancer Research and Clinical Oncology 01/2006; 131(12):773-82. · 2.56 Impact Factor
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ABSTRACT: Abstract
Background
It was reported that elevation of the intracellular concentration of free Ca<sup>2+ </sup>([Ca<sup>2+</sup>]i) by a calcium ionophore increased the release of herpes simplex virus type 1 (HSV-1). Freely diffusible hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) is implied to alter Ca<sup>2+ </sup>homeostasis, which further enhances abnormal cellular activity, causing changes in signal transduction, and cellular dysfunction. Whether H<sub>2</sub>O<sub>2 </sub>could affect [Ca<sup>2+</sup>]i in HSV-1-infected cells had not been investigated.
Results
H<sub>2</sub>O<sub>2 </sub>treatment increased the amount of cell-free virus and decreased the proportion of viable cells. After the treatment, an elevation in [Ca<sup>2+</sup>]i was observed and the increase in [Ca<sup>2+</sup>]i was suppressed when intracellular and cytosolic Ca<sup>2+ </sup>were buffered by Ca<sup>2+ </sup>chelators. In the presence of Ca<sup>2+ </sup>chelators, H<sub>2</sub>O<sub>2</sub>-mediated increases of cell-free virus and cell death were also diminished. Electron microscopic analysis revealed enlarged cell junctions and a focal disintegration of the plasma membrane in H<sub>2</sub>O<sub>2</sub>-treated cells.
Conclusion
These results indicate that H<sub>2</sub>O<sub>2 </sub>can elevate [Ca<sup>2+</sup>]i and induces non-apoptotic cell death with membrane lesions, which is responsible for the increased release of HSV-1 from epithelial cells.
Virology Journal. 01/2006;
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ABSTRACT: Western blotting analysis of mouse nasal tissue using a specific anti-mouse secreted carbonic anhydrase (CA VI) antibody has shown that CA VI is present in this tissue. A single immunoreactive band of 42 kD was observed, as has been found previously for salivary tissues. RT-PCR analysis has shown that nasal mucosa expressed CA VI mRNA. By immunohistochemistry (IHC), CA VI was observed in acinar cells, in duct contents of the anterior gland of the nasal septum, and in the lateral nasal gland. The Bowman's gland, the posterior gland of the nasal septum, and the maxillary sinus gland were negative. Immunoreactivity was also observed in the mucus covering the respiratory and olfactory mucosa and in the lumen of the nasolacrimal duct. In contrast, an anti-rat CA II antibody (that crossreacts with the mouse enzyme) stained only known CA II-positive cells and an occasional olfactory receptor neuron. These results indicate that CA VI is produced by the nasal gland and is secreted over the nasal mucosa. By reversible hydration of CO(2), CA VI is presumed to play a role in mucosal functions such as CO(2) sensation and acid-base balance. It may also play a role in olfactory function as a growth factor in maturation of the olfactory epithelial cells.
Journal of Histochemistry and Cytochemistry 09/2004; 52(8):1057-62. · 2.72 Impact Factor
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ABSTRACT: We described an extremely rare case of adenoid cystic carcinoma associated with salivary duct cyst in the sublingual gland of a 40-year-old Japanese woman. The tumor was growing from the cyst wall and almost occluded the cyst lumen. The epithelium lining the cyst lumen contained both keratin 19-positive cells and alpha-smooth muscle actin-positive cells, indicating the cyst being derived from the acinus/intercalated duct of the sublingual gland. Therefore, our case has presented for the first time a direct evidence that adenoid cystic carcinoma arises from acinus/intercalated duct.
Journal of Oral Pathology and Medicine 06/2004; 33(5):311-3. · 1.63 Impact Factor
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Yusuke Oji,
Hidenori Inohara,
Mitsuhiro Nakazawa,
Yoko Nakano,
Shiro Akahani,
Shin-ichi Nakatsuka,
Satoko Koga,
Ai Ikeba,
Sakie Abeno,
Yuichiro Honjo,
Yoshifumi Yamamoto, Soichi Iwai,
Kaori Yoshida,
Yoshihiro Oka,
Hiroyasu Ogawa,
Jun-ichi Yoshida,
Katsuyuki Aozasa,
Takeshi Kubo,
Haruo Sugiyama
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ABSTRACT: The expression levels of the Wilms' tumor gene WT1 were examined in 56 cases of head and neck squamous cell carcinoma (HNSCC) using quantitative real-time reverse transcriptase-polymerase chain reaction (RT-PCR). They included 4 cases of floor of mouth, 9 of gingiva, 25 of tongue, 10 of oropharynx, 3 of hypopharynx, and 5 larynx squamous cell carcinoma (SCC). All (100%) of 4 cases of floor of mouth, 5 (56%) of 9 gingiva, 17 (68%) of 25 tongue, 8 (80%) of 10 oropharynx, all (100%) of 3 hypopharynx, and all (100%) of 5 larynx SCC overexpressed the WT1 gene in the range of 3.07 x 10(-4)-8.60 x 10(-1) levels (the WT1 expression level in K562 leukemic cells was defined as 1.0). Thus, 42 (75%) out of 56 cases of HNSCC overexpressed the WT1 gene. The high expression level of the WT1 gene significantly correlated with poor histological tumor differentiation and high tumor stage of HNSCC. Immunohistochemical analysis confirmed the expression of WT1 protein in 6 cases (one floor of mouth, 2 tongue, 2 oropharynx, and one larynx SCC) with overexpression of the WT1 gene. The direct sequencing analysis of the WT1 genomic DNA showed no mutations in any of 10 exons of the WT1 gene in 5 different HNSCC. These findings suggest an important role of the wild-type WT1 gene in the tumorigenesis of HNSCC.
Cancer Science 07/2003; 94(6):523-9. · 3.33 Impact Factor
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ABSTRACT: The effect of dual infection with herpes simplex virus type 1 (HSV-1) mutants on human oral squamous cell carcinoma (SCC) cells was examined.
Human oral SCC cells were infected with gamma1(34.5) gene-deficient HSV-1 R849 and HSV-1 HF that has multiple mutations and induces cell fusion. Cell viability was measured by LDH release assay. Athymic mice were injected with oral SCC cells into the buccal region to induce subcutaneous tumors.
Oral SCC cells were infected with R849, followed by infection with R849 or HF. Virus production was elevated by both strains of HSV-1. Although the release of LDH from R849-infected cells was increased by secondary infection with R849 or HF, the effect of HF was more remarkable. When nude mouse tumors were treated with R849, HF, R849+R849, or R849+HF, treatment with R849+HF was the most effective.
These results suggest that fusion-inducing virus HF enhances the oncolytic ability of gamma1(34.5) gene-deficient HSV-1 and provides a rationale for using fusogenic viruses as enhancing agents
Anticancer research 28(6A):3637-45. · 1.73 Impact Factor
